Clinical Trials

One in every 1,000 babies born in the UK experiences mild encephalopathy. These babies are often irritable at birth and may have difficulty with breathing and feeding, but they typically recover within a few days with supportive care. However, recent data suggests that many of these babies may have lower cognitive abilities at age 2, and about 5% may develop severe disability. By school age, nearly 38% require special educational support, which places a significant burden on families. The BAPM recommends that cooling therapy for mild HIE be urgently tested in clinical trials.

The COMET trial aims to evaluate the safety, efficacy, and cost-effectiveness of cooling therapy for babies with mild encephalopathy. The trial will recruit 426 term babies diagnosed with mild HIE from several NHS hospitals, following a detailed neurological examination and aEEG assessment. Babies will be randomly assigned to receive either cooling therapy (for 3 days) or usual care (normothermia) within 6 hours of birth, after informed parental consent. Randomisation will occur at the hospital of birth.

Eligible hospitals must have a servo-controlled cooling device and an aEEG machine. If a baby is born at a non-cooling centre, they will be transferred to a hospital with cooling facilities. All babies will undergo an MRI scan before discharge. The primary outcome will be Bayley IV cognitive scores at age 2, and consent will also be sought for follow-up at school age

Funding: National Institute of Health and Care Research, Health Technology Assessment
Sponsor: Imperial College London

ClinicalTrials.gov Identifier: NCT05889507

Key Documents for the Trial:

• COMET Trial Protocol v4.0
• Parent Information Sheet (PIS) for Main Trial
• PIS for Video Recording of Neurological Assessment
• Informed Consent Form (ICF) for Main Trial
• ICF for Video Recording of Neurological Assessment
• Transport Consent Form: Transfer to Cooling Centre
• Telephone consent form
• Expanded Modified Sarnat staging - SOP (pdf)

 Key reference videos of the Trial:

• Parent information explanatory video
• Expanded Modified Sarnat Stage video explanation.

Comet pilot trial published in Jama

COMET trial pilot randomised controlled trial results published in JAMA Network Open 2024

Erythropoietin  and Darbepoetin alfa are FDA approved drugs for treating anemia, with a proven safety profile in newborn infants and have potential neuroprotective benefits in neonatal encephalopathy. Darbe has similar effects to erythropoietin and requires less frequent administration.
The EDEN trial is a 3 arm randomised control trial and aims to examine the physiological effects of erythropoietin and darbepoetin therapy on proton magnetic resonance spectroscopy thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing cooling therapy.

Funding: National Institute of Health and Care Research
Sponsor: Imperial College London

EMBRACE trial will recruit from several large secondary and tertiary neonatal units in India,
Sri Lanka, and Bangladesh, that cater to a low-income population. All participating neonatal
units will have facilities for providing good supportive neonatal intensive care, including
facilities for ventilation and inotropic support. Dedicated neonatal research nurses will be
appointed at each participating site. All recruiting sites will also have adequate facilities to
ensure research governance. These include a dedicated research office, video conferencing
facilities, protocols and systems for MR scanning and transport, harmonised MR scanners
with the spectroscopy sequences, trained and certified clinical staff on NICHD neurological
examination based on the modified Sarnat stage, and a neurodevelopmental paediatrician to
undertake the Bayley assessment certified for concordance with a gold standard examiner.
The follow up duration is 18-22 months and the planned trial period is 48 months.

Funding: Thrasher Foundation
Sponsor: Imperial College London

The HeartBeat study explored whether heart rate variability (HRV), analyzed using a two-compartment complexity method and machine learning, could be used to stratify encephalopathic infants early after birth. Specifically, the study examined whether HRV could correlate with brain injury detected on MRI and predict adverse neurodevelopmental outcomes at two years of age. This approach has the potential to provide an early and non-invasive method for assessing neonatal brain injury and predicting long-term outcomes.

Funding: National Institute for Health Research (NIHR), UK
Sponsor: Imperial College London

Although cooling is the standard of care for neonatal encephalopathy in high-income countries, the safety and efficacy of cooling in low- and middle-income countries (LMICs) - which shoulder 99% of the disease burden - is unclear.  A total of 408 encephalopathic babies will be randomised to cooling or usual care, from three countries (India, Sri Lanka and Bangladesh). Outcome measures are based on three Tesla MRI and MR spectroscopy at two weeks after birth, and death/neurodisability at 18 months after birth. HELIX is the largest ever cooling trial in the world, and the only such trial to use MR spectroscopy biomarkers across multi-vendor platforms.

Funding:  National Institute of Health and Care Research and Weston Garfield Foundation
Sponsor: Imperial College London

 Helix Study Results

HELIX trial results in Lancet Global Health

Report of the HELIX trial by Nature and expert views 

N-acetyl cysteine (NAC) therapy augments hypothermic neuroprotection in animal models. We are undertaking the early phase studies of this therapy in neonatal encephalopathy, in collaboration with Dr Doe Jenkins at the Medical University of South Carolina. In the first phase of MARINAC, we examined if cerebral glutathione (GSH) levels (via MR spectroscopy), and serum oxidative stress markers (via mass spectrometry), were altered by N-acetyl cysteine. A phase II randomised controlled trial will begin in 2019.

Funding: National Institute of Health and Care Research and BRC
Sponsor: Imperial College London

In this study, we have developed a rapid acquisition method (reduced from 30min to 10min) which could be used across all clinical 3T MRI scanners in the NHS, without the need for specialist software or research agreements with the scanner vendor (this is usually a significant barrier to the widespread implementation of locally developed techniques). We have also developed automated analysis software for the accurate and rapid quantification of the MR spectroscopy data, which will enable all NHS hospitals to use MR spectroscopy in babies with neonatal encephalopathy without the need for a local MR spectroscopy expert.

Funding: National Institute for Health Research (NIHR), UK
Sponsor: Imperial College London

Please see the PREVENT study website for more details

 Summary of the PREVENT study (watch the video link below: Courtesy Sandhya Ramesh, PRINT, Bangalore)

Funding: National Institute for Health Research (NIHR), UK
Sponsor: Imperial College London

PREVENT Study Video